Project Summary As SARS-CoV-2 is sweeping through the USA, healthcare workers (HCW) are our first line of defense. But they too are susceptible to becoming infected, resulting in physical illness, loss of productivity, and potential for disease transmission to patients. Our long-term goal is to protect HCW taking care of SARS-CoV-2-infected patients as well as their families, communities, and the general population. Our specific objective is to rapidly establish a prospective cohort to characterize the factors related to viral transmission and disease severity in a large healthcare system in both healthcare settings and workers' households. Our central hypothesis is that HCW are at higher risk of acquiring and transmitting SARS-CoV-2 and COVID-19 compared with non-healthcare workers (NCHW). We propose to address this hypothesis by recruiting and following 500 HCW and 250 age- and sex-matched NHCW within a large academic health system, Rutgers Biomedical and Health Sciences (RBHS). By intensively following participants over a six-month period and collecting serial biospecimens (nasopharyngeal swabs and blood) and questionnaire data at nine time points, we will be uniquely situated to characterize SARS- CoV-2 transmission and risk factors for COVID-19 among HCW and their families. Our specific aims are: (i), to assess the baseline prevalence of SARS-CoV-2 and COVID-19 in the study population; (ii), to characterize the natural history of SARS-CoV-2 infection in a diverse US workforce, including the incidence of asymptomatic infections and critical illness; (iii), to determine the incidence of SARS-CoV-2 and COVID-19 in healthcare workers compared with non-healthcare workers; (iv), to identify the risk factors for acquiring SARS-CoV-2 and developing COVID-19; (v), to determine the duration and extent of SARS-CoV-2 shedding; and (vi), to determine the rate and direction of transmission of SARS-CoV-2 within households. Our multidisciplinary team has the opportunity, population, resources, and motivation to immediately tackle these crucial questions and to mobilize in the early stages of this public health crisis before overwhelming infection occurs in the US. The proposed cohort study will produce immediate, actionable, and translatable knowledge about protecting the healthcare workforce. The established cohort and repository of ~15,000 biospecimens will also serve as a foundation for future mechanistic studies. The coordinated activities of our team working within a large healthcare system will advance efforts to control, treat, and prevent COVID-19, with focus on the safety of HCW and the staffing of hospitals during this continuing epidemic.